Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Doxil, Caelyx, Doxorubicin, Velcade, Bortezomib
Brief summary
The purpose of this study is to evaluate time to progression, overall survival, response rate and safety for the two open-label treatment groups; DOXIL/CAELYX in combination with VELCADE vs. VELCADE monotherapy.
Detailed description
This is a randomized (study drug assigned by chance), parallel-group, open-label (all involved people know the identity of the intervention), multicenter study in 18 countries. A total of 646 patients with multiple myeloma whose disease has progressed after an initial response to at least 1 line of prior therapy or was refractory to initial treatment will be enrolled. The primary endpoint is time to progression (the interval between the date of randomization and the date of disease progression); secondary endpoints are overall survival (the interval between the date of randomization and the patient's death from any cause), response rate (the proportion of patients in the evaluable population who achieved a complete or partial response), and safety. Other study endpoints include patient reported outcomes and exploratory pharmacogenics (to identify genetic markers of response). Patients are assessed for efficacy and safety every 3 weeks until disease progression is documented or for up to 42 weeks from the start of the first dose of study drug. Patients, who do not progress after the 42-week period, are assessed every 6 weeks until disease progression is documented. Efficacy evaluations includes: serum protein electrophoresis, 24-hour urine collection for protein electrophoresis, skeletal survey (plain films), bone marrow biopsy and aspirate, clinical or radiologic assessment of plasmacytomas, and serum calcium. Responses and progressions are assessed objectively by a computer algorithm based on the EBMT criteria. Safety evaluations include adverse event reports, changes in clinical laboratory findings, and tests for cardiac function (multiple gated acquisition scan/echocardiogram and electrocardiogram). Group A: VELCADE monotherapy: VELCADE 1.3 milligram per meter square (mg/m\^2) to be administered by i.v. bolus on Days 1, 4, 8, and 11 of each 21-day cycle. Group B: DOXIL/VELCADE combination: treated with VELCADE at the same dose and schedule as specified in Group A. DOXIL/CAELYX 30 mg/m\^2 by intravenous infusion given on Day 4 of every 21-day cycle following the administration of VELCADE.
Interventions
1.3 mg/m\^2 by rapid (bolus) i.v. administration given on Days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.
DRUGDoxorubicin hydrochloride (DOXIL/CAELYX)
mg/m\^2 by i.v. infusion will be given on Day 4 of every 21-day cycle after the administration of bortezomib (VELCADE) for up to 8 cycles.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with multiple myeloma who have received at least 1 prior therapy and who have either responded and later had progressive disease or have progressed during their first therapy (primary refractory) are eligible for the study * Patients who may have received prior doxorubicin but not more than a cumulative dose of 240 milligram per meter square (mg/m\^2) doxorubicin, DOXIL, or the equivalent amount of another anthracycline (i.e., 1 mg doxorubicin = 1 mg DOXIL/CAELYX = 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin) * Must have normal cardiac function, as evidenced by a left LVEF within institutional normal limits.
Exclusion criteria
* History of treatment with VELCADE or progressive disease while receiving an anthracycline-containing regimen * No change in disease status during initial therapy * No treatment for malignancy within past 5 yrs (other than multiple myeloma) or progressive disease while receiving anthracycline-containing regimen * Non-secretory disease * Myocardial infarct within past 6 months * No major surgery in past 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | Up to 1 year and 4 months (From date of first participant randomization [20 December 2004] up to interim analysis cut-off date [28 April 2006]) | Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of \>=25% from lowest level in Serum M-component or (the absolute increase must be \>=0.5 gram per deciliter \[g/dL\]); Urine M component or (the absolute increase must be \>=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase \>10 mg/dL. Bone marrow plasma cell percentage \>=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 9 years and 5 months (From date of first participant randomization [20 December 2004] to cut-off date for final survival analysis (16 May 2014) | The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive. |
| Number of Participants With Serious Adverse Events (SAEs) | Up to 1 year and 11 months (From date of first participant randomization [20 December 2004] to cut-off date for safety update (28 November 2006) | A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Czechia, France, Israel, Netherlands, Poland, Portugal, Russia, Singapore, South Africa, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Velcade (Bortezomib) Monotherapy Velcade (bortezomib) 1.3 milligram/meter per square (mg/m\^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. | 322 |
| Doxil/Caelyx Plus Velcade (Bortezomib) Velcade (bortezomib) 1.3 mg/m\^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m\^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles. | 324 |
| Total | 646 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 257 | 253 |
| Overall Study | Lost to Follow-up | 13 | 13 |
| Overall Study | Study closed by sponsor | 34 | 37 |
| Overall Study | Withdrawal by Subject | 18 | 21 |
Baseline characteristics
| Characteristic | Velcade (Bortezomib) Monotherapy | Total | Doxil/Caelyx Plus Velcade (Bortezomib) |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 9.56 | 61.4 years STANDARD_DEVIATION 9.58 | 61.4 years STANDARD_DEVIATION 9.61 |
| Region of Enrollment ARGENTINA | 6 participants | 15 participants | 9 participants |
| Region of Enrollment AUSTRALIA | 31 participants | 62 participants | 31 participants |
| Region of Enrollment AUSTRIA | 12 participants | 18 participants | 6 participants |
| Region of Enrollment BELGIUM-LUXEMBURG | 6 participants | 20 participants | 14 participants |
| Region of Enrollment CANADA | 20 participants | 43 participants | 23 participants |
| Region of Enrollment CZECH REPUBLIC | 14 participants | 36 participants | 22 participants |
| Region of Enrollment FRANCE | 21 participants | 49 participants | 28 participants |
| Region of Enrollment GREAT BRITAIN | 8 participants | 15 participants | 7 participants |
| Region of Enrollment ISRAEL | 25 participants | 46 participants | 21 participants |
| Region of Enrollment ITALY | 17 participants | 28 participants | 11 participants |
| Region of Enrollment NETHERLANDS | 29 participants | 61 participants | 32 participants |
| Region of Enrollment POLAND | 35 participants | 52 participants | 17 participants |
| Region of Enrollment PORTUGAL | 6 participants | 20 participants | 14 participants |
| Region of Enrollment RUSSIA | 38 participants | 72 participants | 34 participants |
| Region of Enrollment SINGAPORE | 3 participants | 5 participants | 2 participants |
| Region of Enrollment SOUTH AFRICA | 13 participants | 28 participants | 15 participants |
| Region of Enrollment SPAIN | 20 participants | 35 participants | 15 participants |
| Region of Enrollment UNITED STATES OF AMERICA | 18 participants | 41 participants | 23 participants |
| Sex: Female, Male Female | 148 Participants | 283 Participants | 135 Participants |
| Sex: Female, Male Male | 174 Participants | 363 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 299 / 318 | 313 / 318 |
| serious Total, serious adverse events | 105 / 318 | 120 / 318 |
Outcome results
Primary
Time to Progression (TTP)
Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of \>=25% from lowest level in Serum M-component or (the absolute increase must be \>=0.5 gram per deciliter \[g/dL\]); Urine M component or (the absolute increase must be \>=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase \>10 mg/dL. Bone marrow plasma cell percentage \>=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.
Time frame: Up to 1 year and 4 months (From date of first participant randomization [20 December 2004] up to interim analysis cut-off date [28 April 2006])
Population: Intent-to-treat (ITT) included all the randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade (Bortezomib) Monotherapy | Time to Progression (TTP) | 6.5 Months |
| Doxil/Caelyx Plus Velcade (Bortezomib) | Time to Progression (TTP) | 9.3 Months |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Up to 1 year and 11 months (From date of first participant randomization [20 December 2004] to cut-off date for safety update (28 November 2006)
Population: Safety population included all the participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade (Bortezomib) Monotherapy | Number of Participants With Serious Adverse Events (SAEs) | 105 Participants |
| Doxil/Caelyx Plus Velcade (Bortezomib) | Number of Participants With Serious Adverse Events (SAEs) | 120 Participants |
Secondary
Overall Survival
The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.
Time frame: Up to 9 years and 5 months (From date of first participant randomization [20 December 2004] to cut-off date for final survival analysis (16 May 2014)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Velcade (Bortezomib) Monotherapy | Overall Survival | 30.8 months |
| Doxil/Caelyx Plus Velcade (Bortezomib) | Overall Survival | 33.0 months |